PCI对急性心肌梗死患者左室重构的影响
|
摘要
背景
急性心肌梗死(acute myocardial infarction, AMI)后机体启动了各种代偿机制,同时开启了左心室重构(left ventricular remodeling, LVRM)的过程,即梗死区室壁心肌的变薄、拉长,产生“膨出”,非梗死区室壁心肌的反应性肥厚、伸长,导致左心室进行性扩张和变形伴心功能降低的过程。在心梗后的心室重构过程中,除心肌细胞本身的结构、代谢及功能异常外,心肌细胞外基质(extracellular matrix, ECM)亦发生异常改变。ECM是存在于细胞之间的动态网状结构,由胶原、蛋白聚糖及糖蛋白等大分子物质组成,参与多种生理和病理过程。心脏胶原基质对维持心肌细胞的排列、协调心肌收缩性及维持左室几何形状起重要作用。ECM成分在基质金属蛋白酶(matrix metalloprotein-ases, MMPs)的水解作用下,处于降解与重组的动态平衡,而金属蛋白酶组织抑制因子(tissue inhibitors of metalloproteinases, TIMPs)是MMPs的内源性特异性抑制剂。冠状动脉再通和心肌再灌注治疗如溶栓和急诊冠状动脉介入(percutaneous coronary intervention,PCI)的尽早实施能最有效的挽救缺血心肌、缩小梗死面积和保护左心功能。本研究旨在对比急诊PCI、延迟PCI及保守治疗,三种不同治疗方案对急性心肌梗死患者心室重构及心功能的影响；反映急性心肌梗死患者基质金属蛋白酶及其抑制物表达变化情况,及其与心梗后心室重构及心功能的相关关系；揭示MMP-9、TIMP-1对心梗后心室重构及心功能的预测作用；进一步探讨PCI对于心室重构的预防作用有无其他分子生物学机制,从其对基质金属蛋白酶及其抑制物表达方面进一步阐明。
目的
1、对比研究急诊PCI、延迟PCI及保守治疗,三种不同治疗方案对急性心肌梗死患者左心室重构的影响,以指导临床治疗,有利于治疗方案的合理选择。
2、研究急性心肌梗死患者基质金属蛋白酶及其抑制物表达变化情况,及其与心梗后左心室重构及心功能的相关关系。即MMP-9、TIMP-1的表达变化情况,与心脏彩色多普勒超声检查及心功能测定相关指标的关系：左心室内径、左心室舒张末和收缩末容积(EDV和ESV)、左心室射血分数(LVEF)、有无心室壁瘤形成等。从而揭示MMP-9、TIMP-1对心梗后心室重构及心功能的预测作用,作为评估的依据。
3、研究PCI对急性心肌梗死患者左心室重构预防作用的机制,其对基质金属蛋白酶及其抑制物表达的影响。再灌注治疗是AMI治疗的关键,AMI早期治疗中最重要的是尽快再灌注治疗,PCI可以限制梗死范围,恢复冬眠心肌的血流灌注,促进心肌梗死区的愈合,防止梗死区心肌的延展和心室重塑。而除此以外,此研究将进一步探讨PCI对于心室重构的预防作用有无其他分子生物学机制,从其对MMPs系统的影响方面进一步阐明。
方法
1、研究对象及分组2010年3月至2010年11月期间在武汉总医院心血管内科住院首次发病AMI患者98例,其中男性70例(71.4%),女性28例(28.6%)。发病12h以内入院的患者51例给予急诊PCI (A组),发病12小时之后的患者22例行延迟PCI (B组)及25例药物保守治疗(C组)。同期冠状动脉造影显示无明显狭窄20例为正常对照组(D组)。AMI各组的年龄、性别构成、合并疾病、危险因素、心梗分型及心梗部位均无显著性差异,具有可比性。
入选标准：1、急性心肌梗死：典型的胸痛症状；心电图相邻两个导联的ST段抬高胸导联≥0.2mV,肢导联≥0.1mV；磷酸肌酸激酶同工酶大于正常两倍以上；以上3个条件中任两项；(2)糖尿病采用美国糖尿病协会ADA2007版诊疗标准：患者既往使用口服降糖药及／或(皮下注射)胰岛素或两次空腹血糖均≥7.0mmol/L,则诊断为糖尿病；(3)高血压诊断采用1999年世界卫生组织／国际高血压联盟(WHO/ISH)标准：在未使用抗高血压药物的情况下,收缩压≥140mmHg,舒张压≥90mmHg;既往有高血压史,目前正在使用抗高血压药物,现血压虽未达到上述水平,亦应诊断为高血压；(4)高血脂诊断标准采用血脂异常防治对策专题组“血脂异常防治建议标准”：TC≥5.72mmol/L; TG≥1.7mmol/L; LDL≥3.64mmol/L; HDL≤0.91mmol/L。
排除标准：陈旧性心肌梗死再发急性心肌梗死、溶栓、结缔组织病、继发性心脏破裂、心肌穿孔、腱索断裂、严重瓣膜病、有创伤的心肺复苏、严重肝肾功能障碍、活动性出血、造影剂过敏、外伤、恶性肿瘤、大手术、各种感染、PCI手术不成功及不能明确持续性胸痛始发时间等情况。
PCI成功标准：(1)冠脉造影显示病变血管残余狭窄<20%；(2)TIMI血流分级达3级：(3)患者自觉症状明显改善；(4)无急性并发症(急诊手术、心肌梗塞或心源性死亡)；(5)住院期间无严重心脏事件(心源性死亡、心肌梗死或再次血管重建术)。
2、研究方法
2.1对每例患者收集病史症状、体格检查、检查心肌酶谱及心电图。如无禁忌所有患者给予强化内科药物治疗,包括：阿司匹林、氯吡格雷、硝酸酯类、血管紧张素转化酶抑制剂或血管紧张素受体阻滞剂、β受体阻断剂、他汀类降脂药等。A组患者入院后立即给予阿司匹林肠溶片(拜阿司匹林)300mg嚼服、氯吡格雷(波立维)600mg口服,在导管室行冠状动脉造影术,对梗死相关动脉病变行PCI(用Innova 2000心血管造影机)。B组择期行延迟PCI,C组给予药物保守治疗。PCI术后患者服用阿司匹林300mg口服1/日、波立维75mg口服1/日,3个月后减为阿司匹林100mg 1/日(坚持服用),波立维75mg 1/日(建议至少服用一年)。(随访期内坚持服用)
2.2、冠状动脉介入手术方法由心内科专科医师完成,按美国心脏病学会和美国心脏协会(ACC/AHA)冠脉造影指南,采用Judkins导管行多角度、多方位选择性冠状动脉造影,使冠脉各段充分显示,目测直径狭窄≥70%判定为靶病变血管。经右侧股动脉或桡动脉途径,行冠脉DES置入术。置入支架后目测原狭窄<20%,且获得TIMI3级血流(CAG评价),则为手术成功。
2.3观察与评价：(1)入院即刻、发病12h、7d、90d穿刺采集周围静脉血6ml,立即3000r/min离心10分钟；立即送本院医学检验科,使用质控均合格的全自动生化测定仪检测血浆总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、空腹血糖(FPG)等。取上清液置-80℃冰箱保存待测。采用酶联免疫法(ELISA)严格按试剂说明操作测血清MMP-9(检测范围0-10ng/ml)、TIMP-1(检测范围0-10ng/ml),试剂由武汉博士德生物工程有限公司提供。(2)所有患者于入院后7-10天及3个月时行二维超声心动图检查及心功能测定相关指标(所用仪器为安捷伦HP5500心脏超声诊断仪,探头频率2-4MHz)。应用双平面或Simpson法计算左心室舒张末和收缩末容积(EDV和ESV)、左心室射血分数(LVEF)、左心室舒张末期内径(LVDd),观察有无心脏室壁瘤形成。
3、统计学处理
采用SPSS 13.0统计软件包进行统计分析,计量资料用x±s表示。计量资料三组间均数比较用单因素方差分析(One-Way ANOVA),两两比较用Games Howell法(方差不齐)或LSD法(方差齐性),组内治疗前后不同时间比较用重复测量或配对t检验。计数资料比较用卡方检验。指标间相关性分析用直线相关分析(Pearson线性相关分析)。P<0.05为统计学差异有显著性意义。制表并描述实验结果。
结果
1、四组间入院基线资料的比较,各组的年龄、性别构成、合并疾病、危险因素、心梗分型、心梗部位均无显著性差异,具有可比性。
2、MMP-9和TIMP-1检测结果
血清MMP-9和TIMP-1浓度在入院即刻三组患者均显著高于正常对照组(3.07±0.87,131.4±39.41,P<0.05)。A组于PCI术后平均MMP-9浓度再次升高,于7d时MMP-9回落至入院水平,与B、C组比较有显著性差异(P<0.05),而TIMP-1至7d时与入院水平无明显差异,高于对照组,90d时有所下降。B组MMP-9浓度于7d时仍显著高于入院时,90d回落至入院水平,与C组比较有显著差异(P<0.05),TIMP-1浓度始终高于对照组,90d时浓度较入院下降。C组MMP-9浓度始终高于入院及对照组,TIMP-1浓度90d时开始下降,但仍高于正常对照组。
3超声心动图分析结果
发病7d时LVEF、EDV、ESV、LVDd在A、B、C三组无显著性差异；发病90d时EDV、ESV及LVDd在A、B组小于C组,并有显著性意义(P<0.05)；90d时LVEF在A、B组大于C组,并有显著性意义(P<0.05)；A、B组LVEF、EDV、ESV及LVDd无显著性差异(P>0.05)。A、B组EDV、ESV、LVDd在90d较7d时减小并有统计学意义；LVEF有所提高但无显著性差异；C组EDV、ESV、LVDd在90d较7d时增大并有显著性差异,LVEF下降并有显著性差异。A、B、C三组间室壁瘤形成比率无显著性差异；90d较7d时有所增加但无显著性差异。
4 MMP-9浓度与心脏超声检查结果相关性
所有患者发病7d时MMP-9浓度与90d时EDV呈显著正相关(r值0.261,P<0.05),与ESV呈显著正相关(r值0.340,P<0.05),与LVEF呈显著负相关(r值-0.218,P<0.05),与LVDd无明显相关性(r值0.118,P>0.05)。
结论
研究结果表明：1、AMI早期患者血清MMP-9浓度升高,可持续一周到数月,再灌注治疗可以降低MMP-9浓度,缩短其持续时间；2、心梗后心室重构过程中,MMP-9浓度与EDV、ESV呈正相关,与LVEF呈负相关,MMP-9浓度也许可以作为AMI发病及心梗后心室重构的预测因子；3、急诊PCI治疗尽早开通犯罪血管可改善心功能,延迟PCI仍可抑制心室重构；4、急性心梗后心室重构早期,EDV、ESV、LVDd较LVEF及室壁瘤形成率更为敏感。
Backgrounds
Many compensatory mechanisms start after acute myocardial infarction,and left ventricular remodeling begins at the same time,which includes that ventricular wall with the infarcted myocardium goes thin and stretched,then produces bulging,and ventricular wall without infarcted myocardium goes reactive hypertrophy and elongation,which results in left ventricular progressive expansion,deformation and cardiac insufficiency.In the process of left ventricular remodeling after acute myocardial infarction, not only the myocardial cell's structure, metabolism and function but also the extracellular matrix become abnormal. Extracellular matrix is hydrolyzed by the matrix etalloproteinases in the dynamic balance of degradation and reorganization,and tissue inhibitors of metalloproteinases is the endogenous specificity inhibitor to it.The therapy of coronary reascularization and myocardial reperfusion, including thrombolysis and acute percutaneous coronary intervention, have been implemented early,which can save ischemic myocardium, narrow infarction area and protect left ventricular function most effectively.The aim of the present study is to contrast different effect of primary percutaneous coronary intervention,delay PCI and conservative treatment on left ventricular remodeling and heart function after acute myocardial infarction.we reveal the expression of matrix etalloproteinases and tissue inhibitors of metalloproteinases after acute myocardial infarction,and the correlationship between MMPs and left ventricular remodeling and heart function, so as to explore predictive value of the MMP-9,TIMP-1 on left ventricular remodeling and heart function.What' more,we'll probe into other molecular biology mechanism in the precautionary effect of PCI on left ventricular remodeling,in terms of influence of PCI on the expression of MMPs and TIMPs.
Objective
1、To contrast different effect of primary PCI, delay PCI and conservative treatment on left ventricular remodeling after acute myocardial infarction, which can guide clinical treatment, and help us get a reasonable selection of treatment.
2、To reflect the expression of matrix etalloproteinases and tissue inhibitors of metalloproteinases after acute myocardial infarction,and the correlationship between MMPs and left ventricular remodeling and heart function. Definitely, to explore the relationship of the MMP-9,TIMP-1 and index standing for left ventricular remodeling and heart function, for example, left ventricular end diastolic diameter (LVDD),left ventricular end diastolic and end systolic volume (EDV and ESV),left ventricular ejection fraction (LVEF) and the formation of ventricular aneurysm.So as to explore the predictive value of the MMP-9 and TIMP-1 on left ventricular remodeling and heart function.
3、To study other molecular biology mechanism in the precautionary effect of PCI on left ventricular remodeling,in terms of influence of PCI on the expression of MMPs and TIMPs. Reperfusion executed as soon as possible is the key to treat AMI. PCI can limit infarction range, restore hibernate myocardial reperfusion, promote the healing myocardial infarction and prevent infarcted myocardium extending and ventricular remodeling. What's more, we'll probe into other molecular biology mechanism in the precautionary effect of PCI on left ventricular remodeling,in terms of influence of PCI on the expression of MMPs. At last we'11 proclaim specific mechanism of left ventricular remodeling,which may be the new target of medication for the left ventricular remodeling.
Methods
1、Object of Study and Grouping Ninety-eight patients with a first acute myocardial infarction were enrolled from March 2010 to Novenber 2010 in Cardiology of Wuhan General Hospital. All of the ninety-eight cases contained seventy men (71.4%) and twenty-eight women (28.6%).Fifty-one patients (group A) were performed primary PCI before 12 hours from onset of symptoms. Twenty-two patients (group B) after 12 hours from onset of symptoms were performed delayed PCI, and twenty-five patients (group C) got conservative therapy. The other twenty patients (group D) composed control group with no obvious stenosis by the CAG (coronary arteriongraphy). There were no significant difference between four groups in sex,age,complication,risk factors,the proportion of two kinds of AMI and locations of myocardial infarction,which were comparable.
Diagnostic criteria:1、AMI:any two of the following three requirements:the typical symptoms of chest pain; st-segment elevation is equal or greater than 0.2 mV in thoracic lead or 0.1 mV in limb lead in two nearby leads in electrocardiogram; Phosphoric acid creatine kinase isozyme is more than twice the normal value; (2) Diabetes is diagnosed according to the ADA 2007 version of standard treatment: Patients with past use of oral hypoglycemic agents and insulin or secondary insulin fasting plasma glucose≥7.0mmol/L, then diagnosed diabetes; (3) Diagnostic criteria for Hypertension adopted in 1999 the World Health Organization/International Society of Hypertension League (WHO/ISH) standard:Without the use of antihypertensive drugs, the systolic blood pressure≥140mmHg, diastolic blood pressure≥90mmHg; past history of high blood pressure, antihypertensive drugs currently in use are not up to the level of blood pressure should be diagnosed as having hypertension; (4) Diagnostic criteria of Hyperlipidemia adopted the Dyslipidemia Control Strategies Thematic Group "proposed standard for prevention and treatment of dyslipidemia":TC≥5.72 mmol/L, TG≥1.7 mmol/L, LDL≥3.64 mmol/L, HDL≤0.91 mmol/L.
Exclusion criteria:except for the patients with recurrence of AMI, thrombolysis, co-nnective tissue disease,secondary cardiac rupture, myocardial perforation, rupture of chordae tendinca, serious valvular disease, a traumatic cardiopulmonary resuscitation (CPR),severe liver and kidney dysfunction,active hemorrhage, hypersensitive to co-ntrast agent, trauma, cancer, major surgery, varieties of infections or it's not clear when persistent chest pain begins,etc.
Success Criteria of PCI:It is compared to a successful operation when the residual stenosis<20% by visual after stenting and the blood level was TIMI3 (CAG assess-ment),and there are no serious complications.
2. Definite Methods
2.1 All patients admitted to hospital were timely collected their medical history and symptoms, and examined physical, serum myocardial enzyme and electrocardiogram. If there is no contraindication, everyone should be given Strengthening medications, containning aspirin, clopidogrel, nitrates, angiotensin 1-converting enzyme inhibitors or angiotensin receptor inhibitors,beta blockers, statins etc.
Group A was given aspirin tablets 300mg and clopidogrel 600mg oral before coronary arteriography and emergency PCI(Innova 2000 Cardiovascular Im aging System)。Group B was given delay PCI; Group C was given conservative treatment. All patients after PCI got Aspirin Enteric-coated Tablets 300mg and clopidogrel 75mg oral once a day,and from 3 months after PCI got Aspirin Enteric-coated Tablets 100mg and clopidogrel 75mg oral once a day at least one year.(insist on taking in the Follow-up period)
2.2 Observation and evaluation
Venipuncture for collection blood 6ml at hospitalization, onset 1 hour,7d and 90d, then centrifuge at 3000r/min about ten minutes;the plasma levels of MMP assay were analyses.Immediately sent them to our laboratory department, and detected the relevant indicators by qualified automatic biochemical locator:Plasma total cholesterol (TC), Triglycerides (TG), high-density lipoprotein cholesterol (hdl-c), low density lipoprotein cholesterol (LDL-C),fasting plasma glucose (FPG),etc.Preservat-ed supernatant in refrigerator at -80℃, then detected serum MMP-9(examination area0-10ng/ml) and TIMP-1(examination area0-10ng/ml), in strict accordance with operating instructions,in enzymoimmunoassay. Wuhan Boster bio-engineering limited company offered the reagent. All of the patients were detected related indicators expressing cardiac function by echocardiography at 7 to 10 days after admission and 3 months(instruments is Agilent HP5500 echocardiographic diagnosis, Probe frequency2-4MHz). Bi-planar or Simpson methodcalculate left ventricular end diastolic diameter (LVDD),left ventricular end diastolic and end systolic volume (EDV and ESV),left ventricular ejection fraction (LVEF) and the formation of ventricular aneurysm.
2.3、Percutaneous Coronary Intervention Surgical Methods
PCI is completed by cardiology specialist according to the The American College Of Cardiology and the American Heart Association (ACC/AHA) guidelines coronary angiography using Judkins method, conventional multi-position (left anterior oblique, right anterior oblique, and axial position cephalopods) projection, in order to make the paragraphs of coronary fully display. Vascular will be judged as target lesion vessel when visually diameter stenosis≥70%, usually through the femoral artery approach, according to standard methods of drug-eluting coronary stent implantation. It is compared to a successful operation when the residual stenosis<20% by visual after stenting and the blood level was TIMI3 (CAG assessment).
3.Statistical Analysis
Datas was processed and analysed by SPSS 13.0 statistical software. All measurement datas were expressed by mean±SD. One-Way ANOVA was used to compare the mean among the three groups as measurement data; multiple comparison by Games Howell (Heterogeneity of variance)或LSD (homogeneity of variance);Paired-Samples T Test or Repeated Measures was used to compare the mean before and after treat; chi-square test was used in enumeration data; the Pearson line correlation analysis was used to detect correlation between index. P<0.05 indicated that the difference was statistically significant. The experimental results were described by tabulation.
Results
1.Comparison of baseline clinical datas between the four groups
The sex, age, proportion of complicating with diabetes, hypertension, hyperlipe-mia and patients with a history of smoking,the proportion of two kinds of AMI and locations of myocardial infarction were not significantly different between the four groups before PCI (P>0.05).
2. Results of Serum MMP-9 and TIMP-1
The concentration of serum MMP-9 and TIMP-1 at hospitalization were significant-ly different between the three groups and the control group (P<0.05).Serum MMP-9 in group A increased again after PCI, and decreased to near normal level at 7d, which was significantly different to B and C groups. But Serum TIMP-1 still exceeded to the control group at 7d,and decline at 90d. Serum MMP-9 in group B at 7d exceeded it significantly at the time of admission,and fell to the level of admission at 90d,which was significantly different to group C (P<0.05), serum TIMP-1 exceeded to the control group all along, the concentration of serum.MMP-9 and TIMP-1 in group C passed the control group significantly (P<0.05)
3.Results from echocardiography.
There were no significant difference among group A、B and C in LVEF、EDV、ESV and LVDd by echocardiography at 7d.The improvement of EDV、ESV、LVDd and LVEF at 90d were statistically significant between A and C groups, the same to B and C groups,but there was no difference between A and B groups (P>0.05). The improvement of EDV、ESV、LVDd in group A and B at 90d were statistically significant to them at 7d,but LVEF wasn't although it got better.The enlargement of EDV、ESV、LVDd in group C at 90d were statistically significant to them at 7d,and LVEF was declined significantly.Ratio of ventricular aneurysm formation increased in group A,B and C at 90d than at 7d,but there was no significance among the three groups.
4. The correlation between density of MMP-9 and results by echocardiographic
The correlation between average serum level of MMP-9 at 7d and EDV、ESV at 90d was positive(r值0.261, P<0.05;r值0.340, P<0.05),and it was negative between average serum level of MMP-9 and LVEF(r值-0.218,P<0.05),and there was no relevance between it and LVDd(r值0.118,P>0.05).
Conclusion
1.Serum MMP-9 in patients with AMI increases and lasts for one week or several months, but PCI can lower it and shorten the time of it;2.During LVRM after AMI,the correlation between average serum level of MMP-9 and EDV、ESV is positive,and the correlation between average serum level of MMP-9 and LVEF is negative. Serum level of MMP-9 become a predictor of heart attack and LVRM after AMI; 3. Direct PCI openning infarct-related artery as early as possible can improve heart function, and delayed PCI can also inhibit left ventricular remodeling;4. EDV、ESV、LVDd are more sensitive than LVEF and ratio of ventricular aneurysm formation in the early stage of left ventricular remodeling after AMI.
急性心肌梗死(acute myocardial infarction, AMI)后机体启动了各种代偿机制,同时开启了左心室重构(left ventricular remodeling, LVRM)的过程,即梗死区室壁心肌的变薄、拉长,产生“膨出”,非梗死区室壁心肌的反应性肥厚、伸长,导致左心室进行性扩张和变形伴心功能降低的过程。在心梗后的心室重构过程中,除心肌细胞本身的结构、代谢及功能异常外,心肌细胞外基质(extracellular matrix, ECM)亦发生异常改变。ECM是存在于细胞之间的动态网状结构,由胶原、蛋白聚糖及糖蛋白等大分子物质组成,参与多种生理和病理过程。心脏胶原基质对维持心肌细胞的排列、协调心肌收缩性及维持左室几何形状起重要作用。ECM成分在基质金属蛋白酶(matrix metalloprotein-ases, MMPs)的水解作用下,处于降解与重组的动态平衡,而金属蛋白酶组织抑制因子(tissue inhibitors of metalloproteinases, TIMPs)是MMPs的内源性特异性抑制剂。冠状动脉再通和心肌再灌注治疗如溶栓和急诊冠状动脉介入(percutaneous coronary intervention,PCI)的尽早实施能最有效的挽救缺血心肌、缩小梗死面积和保护左心功能。本研究旨在对比急诊PCI、延迟PCI及保守治疗,三种不同治疗方案对急性心肌梗死患者心室重构及心功能的影响；反映急性心肌梗死患者基质金属蛋白酶及其抑制物表达变化情况,及其与心梗后心室重构及心功能的相关关系；揭示MMP-9、TIMP-1对心梗后心室重构及心功能的预测作用；进一步探讨PCI对于心室重构的预防作用有无其他分子生物学机制,从其对基质金属蛋白酶及其抑制物表达方面进一步阐明。
目的
1、对比研究急诊PCI、延迟PCI及保守治疗,三种不同治疗方案对急性心肌梗死患者左心室重构的影响,以指导临床治疗,有利于治疗方案的合理选择。
2、研究急性心肌梗死患者基质金属蛋白酶及其抑制物表达变化情况,及其与心梗后左心室重构及心功能的相关关系。即MMP-9、TIMP-1的表达变化情况,与心脏彩色多普勒超声检查及心功能测定相关指标的关系：左心室内径、左心室舒张末和收缩末容积(EDV和ESV)、左心室射血分数(LVEF)、有无心室壁瘤形成等。从而揭示MMP-9、TIMP-1对心梗后心室重构及心功能的预测作用,作为评估的依据。
3、研究PCI对急性心肌梗死患者左心室重构预防作用的机制,其对基质金属蛋白酶及其抑制物表达的影响。再灌注治疗是AMI治疗的关键,AMI早期治疗中最重要的是尽快再灌注治疗,PCI可以限制梗死范围,恢复冬眠心肌的血流灌注,促进心肌梗死区的愈合,防止梗死区心肌的延展和心室重塑。而除此以外,此研究将进一步探讨PCI对于心室重构的预防作用有无其他分子生物学机制,从其对MMPs系统的影响方面进一步阐明。
方法
1、研究对象及分组2010年3月至2010年11月期间在武汉总医院心血管内科住院首次发病AMI患者98例,其中男性70例(71.4%),女性28例(28.6%)。发病12h以内入院的患者51例给予急诊PCI (A组),发病12小时之后的患者22例行延迟PCI (B组)及25例药物保守治疗(C组)。同期冠状动脉造影显示无明显狭窄20例为正常对照组(D组)。AMI各组的年龄、性别构成、合并疾病、危险因素、心梗分型及心梗部位均无显著性差异,具有可比性。
入选标准：1、急性心肌梗死：典型的胸痛症状；心电图相邻两个导联的ST段抬高胸导联≥0.2mV,肢导联≥0.1mV；磷酸肌酸激酶同工酶大于正常两倍以上；以上3个条件中任两项；(2)糖尿病采用美国糖尿病协会ADA2007版诊疗标准：患者既往使用口服降糖药及／或(皮下注射)胰岛素或两次空腹血糖均≥7.0mmol/L,则诊断为糖尿病；(3)高血压诊断采用1999年世界卫生组织／国际高血压联盟(WHO/ISH)标准：在未使用抗高血压药物的情况下,收缩压≥140mmHg,舒张压≥90mmHg;既往有高血压史,目前正在使用抗高血压药物,现血压虽未达到上述水平,亦应诊断为高血压；(4)高血脂诊断标准采用血脂异常防治对策专题组“血脂异常防治建议标准”：TC≥5.72mmol/L; TG≥1.7mmol/L; LDL≥3.64mmol/L; HDL≤0.91mmol/L。
排除标准：陈旧性心肌梗死再发急性心肌梗死、溶栓、结缔组织病、继发性心脏破裂、心肌穿孔、腱索断裂、严重瓣膜病、有创伤的心肺复苏、严重肝肾功能障碍、活动性出血、造影剂过敏、外伤、恶性肿瘤、大手术、各种感染、PCI手术不成功及不能明确持续性胸痛始发时间等情况。
PCI成功标准：(1)冠脉造影显示病变血管残余狭窄<20%；(2)TIMI血流分级达3级：(3)患者自觉症状明显改善；(4)无急性并发症(急诊手术、心肌梗塞或心源性死亡)；(5)住院期间无严重心脏事件(心源性死亡、心肌梗死或再次血管重建术)。
2、研究方法
2.1对每例患者收集病史症状、体格检查、检查心肌酶谱及心电图。如无禁忌所有患者给予强化内科药物治疗,包括：阿司匹林、氯吡格雷、硝酸酯类、血管紧张素转化酶抑制剂或血管紧张素受体阻滞剂、β受体阻断剂、他汀类降脂药等。A组患者入院后立即给予阿司匹林肠溶片(拜阿司匹林)300mg嚼服、氯吡格雷(波立维)600mg口服,在导管室行冠状动脉造影术,对梗死相关动脉病变行PCI(用Innova 2000心血管造影机)。B组择期行延迟PCI,C组给予药物保守治疗。PCI术后患者服用阿司匹林300mg口服1/日、波立维75mg口服1/日,3个月后减为阿司匹林100mg 1/日(坚持服用),波立维75mg 1/日(建议至少服用一年)。(随访期内坚持服用)
2.2、冠状动脉介入手术方法由心内科专科医师完成,按美国心脏病学会和美国心脏协会(ACC/AHA)冠脉造影指南,采用Judkins导管行多角度、多方位选择性冠状动脉造影,使冠脉各段充分显示,目测直径狭窄≥70%判定为靶病变血管。经右侧股动脉或桡动脉途径,行冠脉DES置入术。置入支架后目测原狭窄<20%,且获得TIMI3级血流(CAG评价),则为手术成功。
2.3观察与评价：(1)入院即刻、发病12h、7d、90d穿刺采集周围静脉血6ml,立即3000r/min离心10分钟；立即送本院医学检验科,使用质控均合格的全自动生化测定仪检测血浆总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、空腹血糖(FPG)等。取上清液置-80℃冰箱保存待测。采用酶联免疫法(ELISA)严格按试剂说明操作测血清MMP-9(检测范围0-10ng/ml)、TIMP-1(检测范围0-10ng/ml),试剂由武汉博士德生物工程有限公司提供。(2)所有患者于入院后7-10天及3个月时行二维超声心动图检查及心功能测定相关指标(所用仪器为安捷伦HP5500心脏超声诊断仪,探头频率2-4MHz)。应用双平面或Simpson法计算左心室舒张末和收缩末容积(EDV和ESV)、左心室射血分数(LVEF)、左心室舒张末期内径(LVDd),观察有无心脏室壁瘤形成。
3、统计学处理
采用SPSS 13.0统计软件包进行统计分析,计量资料用x±s表示。计量资料三组间均数比较用单因素方差分析(One-Way ANOVA),两两比较用Games Howell法(方差不齐)或LSD法(方差齐性),组内治疗前后不同时间比较用重复测量或配对t检验。计数资料比较用卡方检验。指标间相关性分析用直线相关分析(Pearson线性相关分析)。P<0.05为统计学差异有显著性意义。制表并描述实验结果。
结果
1、四组间入院基线资料的比较,各组的年龄、性别构成、合并疾病、危险因素、心梗分型、心梗部位均无显著性差异,具有可比性。
2、MMP-9和TIMP-1检测结果
血清MMP-9和TIMP-1浓度在入院即刻三组患者均显著高于正常对照组(3.07±0.87,131.4±39.41,P<0.05)。A组于PCI术后平均MMP-9浓度再次升高,于7d时MMP-9回落至入院水平,与B、C组比较有显著性差异(P<0.05),而TIMP-1至7d时与入院水平无明显差异,高于对照组,90d时有所下降。B组MMP-9浓度于7d时仍显著高于入院时,90d回落至入院水平,与C组比较有显著差异(P<0.05),TIMP-1浓度始终高于对照组,90d时浓度较入院下降。C组MMP-9浓度始终高于入院及对照组,TIMP-1浓度90d时开始下降,但仍高于正常对照组。
3超声心动图分析结果
发病7d时LVEF、EDV、ESV、LVDd在A、B、C三组无显著性差异；发病90d时EDV、ESV及LVDd在A、B组小于C组,并有显著性意义(P<0.05)；90d时LVEF在A、B组大于C组,并有显著性意义(P<0.05)；A、B组LVEF、EDV、ESV及LVDd无显著性差异(P>0.05)。A、B组EDV、ESV、LVDd在90d较7d时减小并有统计学意义；LVEF有所提高但无显著性差异；C组EDV、ESV、LVDd在90d较7d时增大并有显著性差异,LVEF下降并有显著性差异。A、B、C三组间室壁瘤形成比率无显著性差异；90d较7d时有所增加但无显著性差异。
4 MMP-9浓度与心脏超声检查结果相关性
所有患者发病7d时MMP-9浓度与90d时EDV呈显著正相关(r值0.261,P<0.05),与ESV呈显著正相关(r值0.340,P<0.05),与LVEF呈显著负相关(r值-0.218,P<0.05),与LVDd无明显相关性(r值0.118,P>0.05)。
结论
研究结果表明：1、AMI早期患者血清MMP-9浓度升高,可持续一周到数月,再灌注治疗可以降低MMP-9浓度,缩短其持续时间；2、心梗后心室重构过程中,MMP-9浓度与EDV、ESV呈正相关,与LVEF呈负相关,MMP-9浓度也许可以作为AMI发病及心梗后心室重构的预测因子；3、急诊PCI治疗尽早开通犯罪血管可改善心功能,延迟PCI仍可抑制心室重构；4、急性心梗后心室重构早期,EDV、ESV、LVDd较LVEF及室壁瘤形成率更为敏感。
Backgrounds
Many compensatory mechanisms start after acute myocardial infarction,and left ventricular remodeling begins at the same time,which includes that ventricular wall with the infarcted myocardium goes thin and stretched,then produces bulging,and ventricular wall without infarcted myocardium goes reactive hypertrophy and elongation,which results in left ventricular progressive expansion,deformation and cardiac insufficiency.In the process of left ventricular remodeling after acute myocardial infarction, not only the myocardial cell's structure, metabolism and function but also the extracellular matrix become abnormal. Extracellular matrix is hydrolyzed by the matrix etalloproteinases in the dynamic balance of degradation and reorganization,and tissue inhibitors of metalloproteinases is the endogenous specificity inhibitor to it.The therapy of coronary reascularization and myocardial reperfusion, including thrombolysis and acute percutaneous coronary intervention, have been implemented early,which can save ischemic myocardium, narrow infarction area and protect left ventricular function most effectively.The aim of the present study is to contrast different effect of primary percutaneous coronary intervention,delay PCI and conservative treatment on left ventricular remodeling and heart function after acute myocardial infarction.we reveal the expression of matrix etalloproteinases and tissue inhibitors of metalloproteinases after acute myocardial infarction,and the correlationship between MMPs and left ventricular remodeling and heart function, so as to explore predictive value of the MMP-9,TIMP-1 on left ventricular remodeling and heart function.What' more,we'll probe into other molecular biology mechanism in the precautionary effect of PCI on left ventricular remodeling,in terms of influence of PCI on the expression of MMPs and TIMPs.
Objective
1、To contrast different effect of primary PCI, delay PCI and conservative treatment on left ventricular remodeling after acute myocardial infarction, which can guide clinical treatment, and help us get a reasonable selection of treatment.
2、To reflect the expression of matrix etalloproteinases and tissue inhibitors of metalloproteinases after acute myocardial infarction,and the correlationship between MMPs and left ventricular remodeling and heart function. Definitely, to explore the relationship of the MMP-9,TIMP-1 and index standing for left ventricular remodeling and heart function, for example, left ventricular end diastolic diameter (LVDD),left ventricular end diastolic and end systolic volume (EDV and ESV),left ventricular ejection fraction (LVEF) and the formation of ventricular aneurysm.So as to explore the predictive value of the MMP-9 and TIMP-1 on left ventricular remodeling and heart function.
3、To study other molecular biology mechanism in the precautionary effect of PCI on left ventricular remodeling,in terms of influence of PCI on the expression of MMPs and TIMPs. Reperfusion executed as soon as possible is the key to treat AMI. PCI can limit infarction range, restore hibernate myocardial reperfusion, promote the healing myocardial infarction and prevent infarcted myocardium extending and ventricular remodeling. What's more, we'll probe into other molecular biology mechanism in the precautionary effect of PCI on left ventricular remodeling,in terms of influence of PCI on the expression of MMPs. At last we'11 proclaim specific mechanism of left ventricular remodeling,which may be the new target of medication for the left ventricular remodeling.
Methods
1、Object of Study and Grouping Ninety-eight patients with a first acute myocardial infarction were enrolled from March 2010 to Novenber 2010 in Cardiology of Wuhan General Hospital. All of the ninety-eight cases contained seventy men (71.4%) and twenty-eight women (28.6%).Fifty-one patients (group A) were performed primary PCI before 12 hours from onset of symptoms. Twenty-two patients (group B) after 12 hours from onset of symptoms were performed delayed PCI, and twenty-five patients (group C) got conservative therapy. The other twenty patients (group D) composed control group with no obvious stenosis by the CAG (coronary arteriongraphy). There were no significant difference between four groups in sex,age,complication,risk factors,the proportion of two kinds of AMI and locations of myocardial infarction,which were comparable.
Diagnostic criteria:1、AMI:any two of the following three requirements:the typical symptoms of chest pain; st-segment elevation is equal or greater than 0.2 mV in thoracic lead or 0.1 mV in limb lead in two nearby leads in electrocardiogram; Phosphoric acid creatine kinase isozyme is more than twice the normal value; (2) Diabetes is diagnosed according to the ADA 2007 version of standard treatment: Patients with past use of oral hypoglycemic agents and insulin or secondary insulin fasting plasma glucose≥7.0mmol/L, then diagnosed diabetes; (3) Diagnostic criteria for Hypertension adopted in 1999 the World Health Organization/International Society of Hypertension League (WHO/ISH) standard:Without the use of antihypertensive drugs, the systolic blood pressure≥140mmHg, diastolic blood pressure≥90mmHg; past history of high blood pressure, antihypertensive drugs currently in use are not up to the level of blood pressure should be diagnosed as having hypertension; (4) Diagnostic criteria of Hyperlipidemia adopted the Dyslipidemia Control Strategies Thematic Group "proposed standard for prevention and treatment of dyslipidemia":TC≥5.72 mmol/L, TG≥1.7 mmol/L, LDL≥3.64 mmol/L, HDL≤0.91 mmol/L.
Exclusion criteria:except for the patients with recurrence of AMI, thrombolysis, co-nnective tissue disease,secondary cardiac rupture, myocardial perforation, rupture of chordae tendinca, serious valvular disease, a traumatic cardiopulmonary resuscitation (CPR),severe liver and kidney dysfunction,active hemorrhage, hypersensitive to co-ntrast agent, trauma, cancer, major surgery, varieties of infections or it's not clear when persistent chest pain begins,etc.
Success Criteria of PCI:It is compared to a successful operation when the residual stenosis<20% by visual after stenting and the blood level was TIMI3 (CAG assess-ment),and there are no serious complications.
2. Definite Methods
2.1 All patients admitted to hospital were timely collected their medical history and symptoms, and examined physical, serum myocardial enzyme and electrocardiogram. If there is no contraindication, everyone should be given Strengthening medications, containning aspirin, clopidogrel, nitrates, angiotensin 1-converting enzyme inhibitors or angiotensin receptor inhibitors,beta blockers, statins etc.
Group A was given aspirin tablets 300mg and clopidogrel 600mg oral before coronary arteriography and emergency PCI(Innova 2000 Cardiovascular Im aging System)。Group B was given delay PCI; Group C was given conservative treatment. All patients after PCI got Aspirin Enteric-coated Tablets 300mg and clopidogrel 75mg oral once a day,and from 3 months after PCI got Aspirin Enteric-coated Tablets 100mg and clopidogrel 75mg oral once a day at least one year.(insist on taking in the Follow-up period)
2.2 Observation and evaluation
Venipuncture for collection blood 6ml at hospitalization, onset 1 hour,7d and 90d, then centrifuge at 3000r/min about ten minutes;the plasma levels of MMP assay were analyses.Immediately sent them to our laboratory department, and detected the relevant indicators by qualified automatic biochemical locator:Plasma total cholesterol (TC), Triglycerides (TG), high-density lipoprotein cholesterol (hdl-c), low density lipoprotein cholesterol (LDL-C),fasting plasma glucose (FPG),etc.Preservat-ed supernatant in refrigerator at -80℃, then detected serum MMP-9(examination area0-10ng/ml) and TIMP-1(examination area0-10ng/ml), in strict accordance with operating instructions,in enzymoimmunoassay. Wuhan Boster bio-engineering limited company offered the reagent. All of the patients were detected related indicators expressing cardiac function by echocardiography at 7 to 10 days after admission and 3 months(instruments is Agilent HP5500 echocardiographic diagnosis, Probe frequency2-4MHz). Bi-planar or Simpson methodcalculate left ventricular end diastolic diameter (LVDD),left ventricular end diastolic and end systolic volume (EDV and ESV),left ventricular ejection fraction (LVEF) and the formation of ventricular aneurysm.
2.3、Percutaneous Coronary Intervention Surgical Methods
PCI is completed by cardiology specialist according to the The American College Of Cardiology and the American Heart Association (ACC/AHA) guidelines coronary angiography using Judkins method, conventional multi-position (left anterior oblique, right anterior oblique, and axial position cephalopods) projection, in order to make the paragraphs of coronary fully display. Vascular will be judged as target lesion vessel when visually diameter stenosis≥70%, usually through the femoral artery approach, according to standard methods of drug-eluting coronary stent implantation. It is compared to a successful operation when the residual stenosis<20% by visual after stenting and the blood level was TIMI3 (CAG assessment).
3.Statistical Analysis
Datas was processed and analysed by SPSS 13.0 statistical software. All measurement datas were expressed by mean±SD. One-Way ANOVA was used to compare the mean among the three groups as measurement data; multiple comparison by Games Howell (Heterogeneity of variance)或LSD (homogeneity of variance);Paired-Samples T Test or Repeated Measures was used to compare the mean before and after treat; chi-square test was used in enumeration data; the Pearson line correlation analysis was used to detect correlation between index. P<0.05 indicated that the difference was statistically significant. The experimental results were described by tabulation.
Results
1.Comparison of baseline clinical datas between the four groups
The sex, age, proportion of complicating with diabetes, hypertension, hyperlipe-mia and patients with a history of smoking,the proportion of two kinds of AMI and locations of myocardial infarction were not significantly different between the four groups before PCI (P>0.05).
2. Results of Serum MMP-9 and TIMP-1
The concentration of serum MMP-9 and TIMP-1 at hospitalization were significant-ly different between the three groups and the control group (P<0.05).Serum MMP-9 in group A increased again after PCI, and decreased to near normal level at 7d, which was significantly different to B and C groups. But Serum TIMP-1 still exceeded to the control group at 7d,and decline at 90d. Serum MMP-9 in group B at 7d exceeded it significantly at the time of admission,and fell to the level of admission at 90d,which was significantly different to group C (P<0.05), serum TIMP-1 exceeded to the control group all along, the concentration of serum.MMP-9 and TIMP-1 in group C passed the control group significantly (P<0.05)
3.Results from echocardiography.
There were no significant difference among group A、B and C in LVEF、EDV、ESV and LVDd by echocardiography at 7d.The improvement of EDV、ESV、LVDd and LVEF at 90d were statistically significant between A and C groups, the same to B and C groups,but there was no difference between A and B groups (P>0.05). The improvement of EDV、ESV、LVDd in group A and B at 90d were statistically significant to them at 7d,but LVEF wasn't although it got better.The enlargement of EDV、ESV、LVDd in group C at 90d were statistically significant to them at 7d,and LVEF was declined significantly.Ratio of ventricular aneurysm formation increased in group A,B and C at 90d than at 7d,but there was no significance among the three groups.
4. The correlation between density of MMP-9 and results by echocardiographic
The correlation between average serum level of MMP-9 at 7d and EDV、ESV at 90d was positive(r值0.261, P<0.05;r值0.340, P<0.05),and it was negative between average serum level of MMP-9 and LVEF(r值-0.218,P<0.05),and there was no relevance between it and LVDd(r值0.118,P>0.05).
Conclusion
1.Serum MMP-9 in patients with AMI increases and lasts for one week or several months, but PCI can lower it and shorten the time of it;2.During LVRM after AMI,the correlation between average serum level of MMP-9 and EDV、ESV is positive,and the correlation between average serum level of MMP-9 and LVEF is negative. Serum level of MMP-9 become a predictor of heart attack and LVRM after AMI; 3. Direct PCI openning infarct-related artery as early as possible can improve heart function, and delayed PCI can also inhibit left ventricular remodeling;4. EDV、ESV、LVDd are more sensitive than LVEF and ratio of ventricular aneurysm formation in the early stage of left ventricular remodeling after AMI.
引文
[1]Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloprote-inases-Structure, function, and biochemistry [J].Circulation Research, 2003,92(8):827-839.
[2]Kaden JJ,Dempfle CE,Sueselbeck T,et al,Time-dependent in the plasma conc-entrat disruption of the myocardial extracellulation of matrix metalloproteinase-9 after acute myocardial infarction[J].Cardiology,2003,99(3):140-144.
[3]Heymans S,Luttun A,Nuyens D,et al.Inhibition of plasminogen activators or matrix metalloproteases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure[J].Nat Med,1999,5(10):1135-1142.
[4]Ducharme A,Frantz S,Aikawa M,et al.Targeted delection of matrix etalloprotein-ase-9 attcunat-Es left ventricular enlargement and collagen accumelation after experi- mental myocardial infaretionor[J].J Clin Invest,2000,106(1):55-62.
[5]Peterson JT,Li H,Dillon L,et al.Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infracted rat[J].Cardiovasc Res,2000,46(2):307-315.
[6]Fedak PW,Altamentova SM,Weisel RD,et al.Matrix remodeling in experimental and human heart failure:a possible regulatory role for TIMP-3[J].Am J Phsiol,2003, 284:626-634.
[7]Deten A,Holzl A,Leicht M.Changes in extracellularmatrix and in transforming growth factor beta isoforms after coronary artery ligation in rats[J].J Mol Cell Cardiol,2001,33(6):1191-1207.
[8]Creemers EE,Davis JN,Parkhurst AM, et al.Difficiency of tissue inhibitor of matrix metalloproteinase lexacerbates LV remodeling following myocardial infarction in mice[J].Am J Physiol,2003,284(l):H364-371.
[9]Polonski L,Gasior M,Wasilewski J,et al.Outcome of primary coronary angioplasty and angioplasty after initial thrombolysis in the treatment of 374 consecutive patients with acute myocardial infarction[J].Am Heart J,2003,145(5):855-861.
[10]Keeley EC,Boura JA,Grines CL.Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction:a quantitative review of 23 randomized trials[J].Lancet,2003,361(9351):13-20.
[11]Saia F,Lemos PA,Lee CH,et al.Sirolimus-eluting stent implantation in ST elevat-eon acute myocardial infarction:a clinical and angiographic study [J]. Circulation, 2003,108(16):1927-1929.
[12]Braunwald E,Rutherford JD.Reversible ischemic left ventricular dysfunction: evidence for the "hibernating myocardium"[J].J Am Coll Cardiol,1986,8(6):1467-1470.
[13]Hirayama A,Kusuoka H,Adachi T,et al.Comparison of time of reperfusion during anterior wall acute myocardial infarction to left ventricular volume one month and 20 month later[J].Am J Cardiol,2002,89(12):1335-1340.
[14]Sadanandan S,Buller C,Menon V,et al.The late open artery hypothesis-a decade later[J].Am Heart J,2001,142(3):411-421.
[15]Miyazaki S, Kasai T, Miyauchi K, et al.Changes of matrix metalloproteinase-9 level is associated with left ventricular remodeling following acute myocardial infarction among patients treated with trandolapril, valsartan or both[J].Circ J. 2010,74(6):1158-1164.
[16]Zhang P, Yang YJ, Chen X, et al.Comparison of doxycycline, losartan, and their combination on the expression of matrix metalloproteinase, tissue inhibitor of matrix metalloproteinase, and collagen remodeling in the noninfarcted myocardium after acute myocardial infarction in rat [J].Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2005,27(1):53-61.
[17]Mustonen E, Leskinen H, Aro J, et al.Metoprolol treatment lowers thrombospondin-4 expression in rats with myocardial infarction and left ventricular hypertrophy[J].Basic Clin Pharmacol Toxicol.2010,107(3):709-717.
[18]Yasuda S, Miyazaki S, Kinoshita H, et al. Enhanced cardiac production of matrix metalloproteinase-2 and -9 and its attenuation associated with pravastatin treatment in patients with acute myocardial infarction [J].Clin Sci (Lond).2007,112(1):43-49.
[19]Kayrak M, Bacaksiz A, Vatankulu MA, et al.The effects of spironolactone on atrial remodeling in patients with preserved left ventricular function after an acute myocardial infarction:a randomized follow-up study[J].Coron Artery Dis.2010,21 (8):477-485.
[20]Weir RA, Mark PB, Petrie CJ, et al.Left ventricular remodeling after acute myocardial infarction:does eplerenone have an effect? [J].Am Heart J.2009,157(6): 1088-1096.
[21]Iraqi W, Rossignol P, Angioi M, et al.Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure:insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study[J].Circulation.2009,12; 119(18):2471-2479.
[1]Kelly D, Khan SQ, Thompson M, et al.Plasma tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9:novel indicators of left ventricular remodelling and prognosis after acute myocardial infarction[J]. Eur Heart J.2008,29(17):2116-24.
[2]Furenes EB, Arnesen H, Solheim S, et al.The profile of circulating metalloprotein-ases after PCI in patients with acute myocardial infarction or stable angina[J]. Thromb Res.2009,124(5):560-4.
[3]Polonski L,Gasior M,Wasilewski J,et al.Outcome of primary coronary angioplasty and angioplasty after initial thrombolysis in the treatment of 374 consecutive patients with acute myocardial infarction[J].Am Heart J,2003,145(5):855-861.
[4]Keeley EC,Boura JA,Grines CL.Primary angioplasty versus intravenous thromboly-tic therapy for acute myocardial infarction:a quantitative review of 23 randomized trials[J].Lancet,2003,361(9351):13-20.
[5]Saia F,Lemos PA,Lee CH,et al.Sirolimus-eluting stent implantation in ST elevation acute myocardial infarction:a clinical and angiographic study[J].Circulation,2003,108 (16):1927-1929.
[6]Hirayama A,Kusuoka H,Adachi T,et al.Comparison of time of reperfusion during anterior wall acute myocardial infarction to left ventricular volume one month and 20 month later[J].Am J Cardiol,2002,89(12):1335-1340.
[7]Sadanandan S,Buller C,Menon V,et al.The late open artery hypothesis-a decade later[J].Am Heart J,2001,142(3):411-421.
[8]Zhang P, Yang YJ, Chen X, et al.Comparison of doxycycline, losartan, and their combination on the expression of matrix metalloproteinase, tissue inhibitor of matrix metalloproteinase, and collagen remodeling in the noninfarcted myocardium after acute myocardial infarction in rat[J]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao.2005, 27(1):53-61.
[9]Yasuda S, Miyazaki S, Kinoshita H, et al. Enhanced cardiac production of matrix metalloproteinase-2 and -9 and its attenuation associated with pravastatin treatment in patients with acute myocardial infarction[J]. Nonogi H.Clin Sci (Lond).2007, 112(1):43-9.
[10]Miyazaki S, Kasai T, Miyauchi K, et al.Changes of matrix metalloproteinase-9 level is associated with left ventricular remodeling following acute myocardial infarction among patients treated with trandolapril, valsartan or both[J].Circ J.2010,74(6):1158-64.
[11]Jiang B, Chen J, Xu L, et al.Salvianolic acid B functioned as a competitive inhibitor of matrix metalloproteinase-9 and efficiently prevented cardiac remodeling [J].BMC Pharmacol.2010,25; 10:10.
[12]Krishnamurthy P, Peterson JT, Subramanian V, et al.Inhibition of matrix metallo-proteinases improves left ventricular function in mice lacking osteopontin after myocardial infarction[J].Mol Cell Biochem.2009,322(1-2):53-62.
[13]Kandalam V, Basu R, Abraham T, et al.Early activation of matrix metalloprotein-ases underlies the exacerbated systolic and diastolic dysfunction in mice lacking TIMP3 following myocardial infarction[J].Am J Physiol Heart Circ Physiol.2010,299(4):H1012-1023.
[14]Shu T, Zeng B, Ren X, et al.HO-1 modified mesenchymal stem cells modulate MMPs/TIMPs system and adverse remodeling in infarcted myocardium[J].Tissue Cell. 2010,42(4):217-222.
[15]Reddy VS, Prabhu SD, Mummidi S, et al.Interleukin-18 induces EMMPRIN expression in primary cardiomyocytes via JNK/Spl signaling and MMP-9 in part via EMMPRIN and through AP-1 and NF-kappaB activation[J]. Am J Physiol Heart Circ Physiol.2010,299(4):H1242-1254.
[1]王宝华,司忠义.基质金属蛋白酶与血管损伤后再狭窄的研究现状[J].心脏杂志,2007,19(4)：481-483.
[2]张庆成,侯燕,汪承炜,等.CD40L和基质金属蛋白酶在冠脉斑块形成中的作用机制临床研究[J].武警医学,2008,19(5)：426-428.
[3]崔艳,邓丽华,白露,等.血清白细胞介素-18和基质金属蛋白酶-2对急性冠脉综合症的临床意义[J].中国急救医学,2007,27(12)：1117-1119.
[4]王绍欣,董平栓,杨旭明,等.急性冠脉综合症患者冠状动脉血及外周血血浆基质金属蛋白酶-9水平检测[J].郑州大学学报,2006,41(6)：1092-1094.
[5]殷忠,李兰荪,张荣怀,等.急性冠脉综上所述合征患者外周血MMP-9及CRP的变化及其临床意义[J].心脏杂志,2006,18(3)：318-319,322.
[6]戴锋,肖桂林,潘静,等.急性心肌梗死患者PCI术前后血清基质金属蛋 白酶-2与基质金属蛋白酶-9的相关性[J].细胞与分子免疫学杂志,2009,25(8)：716-718.
[7]李昭,李梦,胡健,等.冠状动脉支架植入对冠心病患者血清基质金属蛋白酶2表达的影响[J].中国动脉硬化杂志,2008,16(5)：392-394.
[8]Yasuda S,Miyazaki S, Kinoshita H, et al. Enhanced cardiac production of matrix metalloprretteinase-2 and-9 and its attenuation associated with pravastat in treatment in patients with acute myocardial infarction[J].ClinSci (Lond),2007,112(1)43-49.
[9]徐新生,沈彦明,宋建军,等.冠状动脉支架术对冠心病患者血小板活化功能的影响[J].中国动脉硬化杂志,2006,14(11)：45-48.
[10]周秀艳,侯振江,李艳华,等.血清基质金属蛋白酶—2及其组织抑制因子-1与糖尿病高血压和肾病的相关性研究[J].中国老年学杂志,2006,26(4)：458-460.
[11]Thrailkill KM, Bunn RC, Moreau CS, et al. Matrix metalloproteinase-2 dysregu-lation in type 1 diabetes.[J].Diabetes care,2007,30(9):2321-2326.
[12]Rysz J, Banach M, Stolarek RA, et al.Serum matrix metalloproteinases MMP-2 and MMP-9 and metal loproteinase tissue inhibitors TIMP-1 and TIMP-2 in diabetic nephropathy [J].Journal ofNephrology,2007,20(4):444-452.
[13]Lauhio A, Sorsa T, Srinivas R, et al. Urinary matrix metalloproteinase-8,-9,-14 and their regulators (TRY-1, TRY-2, TATI) in patients with diabetic nephropathy[J]. Annals Medicine,2008,40(4):312-320.
[14]Thrailkill KM, Clay Bunn R, Fowlkes JL.Matrix metalloproteinases:their pote-ntial role in the pathogenesis of diabetic nephropathy [J].Endocrine,2009,35(1):1-10.
[15]崔燕,孟晓萍,张晶,等.血清基质金属蛋白酶在老年冠心病合并糖尿病肾病的表达[J].中国老年学杂志,2007,27(16)：1600-1601.
[16]崔燕,孟晓萍,杨东华,等.冠心病并发糖尿病肾病患者血清基质金属蛋白酶-2(MMP-2)的表达及临床意义[J].中国实验诊断学,2007,11(10)：1327- 1329.
[17]葛焕琦,马彦,孟晓萍,等.合并血管病变的2型糖尿病患者血清基质金属蛋白酶2水平观察[J].中国糖尿病杂志,2007,15(5)：303-304.
[2]Kaden JJ,Dempfle CE,Sueselbeck T,et al,Time-dependent in the plasma conc-entrat disruption of the myocardial extracellulation of matrix metalloproteinase-9 after acute myocardial infarction[J].Cardiology,2003,99(3):140-144.
[3]Heymans S,Luttun A,Nuyens D,et al.Inhibition of plasminogen activators or matrix metalloproteases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure[J].Nat Med,1999,5(10):1135-1142.
[4]Ducharme A,Frantz S,Aikawa M,et al.Targeted delection of matrix etalloprotein-ase-9 attcunat-Es left ventricular enlargement and collagen accumelation after experi- mental myocardial infaretionor[J].J Clin Invest,2000,106(1):55-62.
[5]Peterson JT,Li H,Dillon L,et al.Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infracted rat[J].Cardiovasc Res,2000,46(2):307-315.
[6]Fedak PW,Altamentova SM,Weisel RD,et al.Matrix remodeling in experimental and human heart failure:a possible regulatory role for TIMP-3[J].Am J Phsiol,2003, 284:626-634.
[7]Deten A,Holzl A,Leicht M.Changes in extracellularmatrix and in transforming growth factor beta isoforms after coronary artery ligation in rats[J].J Mol Cell Cardiol,2001,33(6):1191-1207.
[8]Creemers EE,Davis JN,Parkhurst AM, et al.Difficiency of tissue inhibitor of matrix metalloproteinase lexacerbates LV remodeling following myocardial infarction in mice[J].Am J Physiol,2003,284(l):H364-371.
[9]Polonski L,Gasior M,Wasilewski J,et al.Outcome of primary coronary angioplasty and angioplasty after initial thrombolysis in the treatment of 374 consecutive patients with acute myocardial infarction[J].Am Heart J,2003,145(5):855-861.
[10]Keeley EC,Boura JA,Grines CL.Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction:a quantitative review of 23 randomized trials[J].Lancet,2003,361(9351):13-20.
[11]Saia F,Lemos PA,Lee CH,et al.Sirolimus-eluting stent implantation in ST elevat-eon acute myocardial infarction:a clinical and angiographic study [J]. Circulation, 2003,108(16):1927-1929.
[12]Braunwald E,Rutherford JD.Reversible ischemic left ventricular dysfunction: evidence for the "hibernating myocardium"[J].J Am Coll Cardiol,1986,8(6):1467-1470.
[13]Hirayama A,Kusuoka H,Adachi T,et al.Comparison of time of reperfusion during anterior wall acute myocardial infarction to left ventricular volume one month and 20 month later[J].Am J Cardiol,2002,89(12):1335-1340.
[14]Sadanandan S,Buller C,Menon V,et al.The late open artery hypothesis-a decade later[J].Am Heart J,2001,142(3):411-421.
[15]Miyazaki S, Kasai T, Miyauchi K, et al.Changes of matrix metalloproteinase-9 level is associated with left ventricular remodeling following acute myocardial infarction among patients treated with trandolapril, valsartan or both[J].Circ J. 2010,74(6):1158-1164.
[16]Zhang P, Yang YJ, Chen X, et al.Comparison of doxycycline, losartan, and their combination on the expression of matrix metalloproteinase, tissue inhibitor of matrix metalloproteinase, and collagen remodeling in the noninfarcted myocardium after acute myocardial infarction in rat [J].Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2005,27(1):53-61.
[17]Mustonen E, Leskinen H, Aro J, et al.Metoprolol treatment lowers thrombospondin-4 expression in rats with myocardial infarction and left ventricular hypertrophy[J].Basic Clin Pharmacol Toxicol.2010,107(3):709-717.
[18]Yasuda S, Miyazaki S, Kinoshita H, et al. Enhanced cardiac production of matrix metalloproteinase-2 and -9 and its attenuation associated with pravastatin treatment in patients with acute myocardial infarction [J].Clin Sci (Lond).2007,112(1):43-49.
[19]Kayrak M, Bacaksiz A, Vatankulu MA, et al.The effects of spironolactone on atrial remodeling in patients with preserved left ventricular function after an acute myocardial infarction:a randomized follow-up study[J].Coron Artery Dis.2010,21 (8):477-485.
[20]Weir RA, Mark PB, Petrie CJ, et al.Left ventricular remodeling after acute myocardial infarction:does eplerenone have an effect? [J].Am Heart J.2009,157(6): 1088-1096.
[21]Iraqi W, Rossignol P, Angioi M, et al.Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure:insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study[J].Circulation.2009,12; 119(18):2471-2479.
[1]Kelly D, Khan SQ, Thompson M, et al.Plasma tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9:novel indicators of left ventricular remodelling and prognosis after acute myocardial infarction[J]. Eur Heart J.2008,29(17):2116-24.
[2]Furenes EB, Arnesen H, Solheim S, et al.The profile of circulating metalloprotein-ases after PCI in patients with acute myocardial infarction or stable angina[J]. Thromb Res.2009,124(5):560-4.
[3]Polonski L,Gasior M,Wasilewski J,et al.Outcome of primary coronary angioplasty and angioplasty after initial thrombolysis in the treatment of 374 consecutive patients with acute myocardial infarction[J].Am Heart J,2003,145(5):855-861.
[4]Keeley EC,Boura JA,Grines CL.Primary angioplasty versus intravenous thromboly-tic therapy for acute myocardial infarction:a quantitative review of 23 randomized trials[J].Lancet,2003,361(9351):13-20.
[5]Saia F,Lemos PA,Lee CH,et al.Sirolimus-eluting stent implantation in ST elevation acute myocardial infarction:a clinical and angiographic study[J].Circulation,2003,108 (16):1927-1929.
[6]Hirayama A,Kusuoka H,Adachi T,et al.Comparison of time of reperfusion during anterior wall acute myocardial infarction to left ventricular volume one month and 20 month later[J].Am J Cardiol,2002,89(12):1335-1340.
[7]Sadanandan S,Buller C,Menon V,et al.The late open artery hypothesis-a decade later[J].Am Heart J,2001,142(3):411-421.
[8]Zhang P, Yang YJ, Chen X, et al.Comparison of doxycycline, losartan, and their combination on the expression of matrix metalloproteinase, tissue inhibitor of matrix metalloproteinase, and collagen remodeling in the noninfarcted myocardium after acute myocardial infarction in rat[J]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao.2005, 27(1):53-61.
[9]Yasuda S, Miyazaki S, Kinoshita H, et al. Enhanced cardiac production of matrix metalloproteinase-2 and -9 and its attenuation associated with pravastatin treatment in patients with acute myocardial infarction[J]. Nonogi H.Clin Sci (Lond).2007, 112(1):43-9.
[10]Miyazaki S, Kasai T, Miyauchi K, et al.Changes of matrix metalloproteinase-9 level is associated with left ventricular remodeling following acute myocardial infarction among patients treated with trandolapril, valsartan or both[J].Circ J.2010,74(6):1158-64.
[11]Jiang B, Chen J, Xu L, et al.Salvianolic acid B functioned as a competitive inhibitor of matrix metalloproteinase-9 and efficiently prevented cardiac remodeling [J].BMC Pharmacol.2010,25; 10:10.
[12]Krishnamurthy P, Peterson JT, Subramanian V, et al.Inhibition of matrix metallo-proteinases improves left ventricular function in mice lacking osteopontin after myocardial infarction[J].Mol Cell Biochem.2009,322(1-2):53-62.
[13]Kandalam V, Basu R, Abraham T, et al.Early activation of matrix metalloprotein-ases underlies the exacerbated systolic and diastolic dysfunction in mice lacking TIMP3 following myocardial infarction[J].Am J Physiol Heart Circ Physiol.2010,299(4):H1012-1023.
[14]Shu T, Zeng B, Ren X, et al.HO-1 modified mesenchymal stem cells modulate MMPs/TIMPs system and adverse remodeling in infarcted myocardium[J].Tissue Cell. 2010,42(4):217-222.
[15]Reddy VS, Prabhu SD, Mummidi S, et al.Interleukin-18 induces EMMPRIN expression in primary cardiomyocytes via JNK/Spl signaling and MMP-9 in part via EMMPRIN and through AP-1 and NF-kappaB activation[J]. Am J Physiol Heart Circ Physiol.2010,299(4):H1242-1254.
[1]王宝华,司忠义.基质金属蛋白酶与血管损伤后再狭窄的研究现状[J].心脏杂志,2007,19(4)：481-483.
[2]张庆成,侯燕,汪承炜,等.CD40L和基质金属蛋白酶在冠脉斑块形成中的作用机制临床研究[J].武警医学,2008,19(5)：426-428.
[3]崔艳,邓丽华,白露,等.血清白细胞介素-18和基质金属蛋白酶-2对急性冠脉综合症的临床意义[J].中国急救医学,2007,27(12)：1117-1119.
[4]王绍欣,董平栓,杨旭明,等.急性冠脉综合症患者冠状动脉血及外周血血浆基质金属蛋白酶-9水平检测[J].郑州大学学报,2006,41(6)：1092-1094.
[5]殷忠,李兰荪,张荣怀,等.急性冠脉综上所述合征患者外周血MMP-9及CRP的变化及其临床意义[J].心脏杂志,2006,18(3)：318-319,322.
[6]戴锋,肖桂林,潘静,等.急性心肌梗死患者PCI术前后血清基质金属蛋 白酶-2与基质金属蛋白酶-9的相关性[J].细胞与分子免疫学杂志,2009,25(8)：716-718.
[7]李昭,李梦,胡健,等.冠状动脉支架植入对冠心病患者血清基质金属蛋白酶2表达的影响[J].中国动脉硬化杂志,2008,16(5)：392-394.
[8]Yasuda S,Miyazaki S, Kinoshita H, et al. Enhanced cardiac production of matrix metalloprretteinase-2 and-9 and its attenuation associated with pravastat in treatment in patients with acute myocardial infarction[J].ClinSci (Lond),2007,112(1)43-49.
[9]徐新生,沈彦明,宋建军,等.冠状动脉支架术对冠心病患者血小板活化功能的影响[J].中国动脉硬化杂志,2006,14(11)：45-48.
[10]周秀艳,侯振江,李艳华,等.血清基质金属蛋白酶—2及其组织抑制因子-1与糖尿病高血压和肾病的相关性研究[J].中国老年学杂志,2006,26(4)：458-460.
[11]Thrailkill KM, Bunn RC, Moreau CS, et al. Matrix metalloproteinase-2 dysregu-lation in type 1 diabetes.[J].Diabetes care,2007,30(9):2321-2326.
[12]Rysz J, Banach M, Stolarek RA, et al.Serum matrix metalloproteinases MMP-2 and MMP-9 and metal loproteinase tissue inhibitors TIMP-1 and TIMP-2 in diabetic nephropathy [J].Journal ofNephrology,2007,20(4):444-452.
[13]Lauhio A, Sorsa T, Srinivas R, et al. Urinary matrix metalloproteinase-8,-9,-14 and their regulators (TRY-1, TRY-2, TATI) in patients with diabetic nephropathy[J]. Annals Medicine,2008,40(4):312-320.
[14]Thrailkill KM, Clay Bunn R, Fowlkes JL.Matrix metalloproteinases:their pote-ntial role in the pathogenesis of diabetic nephropathy [J].Endocrine,2009,35(1):1-10.
[15]崔燕,孟晓萍,张晶,等.血清基质金属蛋白酶在老年冠心病合并糖尿病肾病的表达[J].中国老年学杂志,2007,27(16)：1600-1601.
[16]崔燕,孟晓萍,杨东华,等.冠心病并发糖尿病肾病患者血清基质金属蛋白酶-2(MMP-2)的表达及临床意义[J].中国实验诊断学,2007,11(10)：1327- 1329.
[17]葛焕琦,马彦,孟晓萍,等.合并血管病变的2型糖尿病患者血清基质金属蛋白酶2水平观察[J].中国糖尿病杂志,2007,15(5)：303-304.